Insulin Sensitivity in Men With the Metabolic Syndrome

Not Applicable

Suspended

• Conditions: Metabolic Syndrome
• Interventions: Procedure: intravenous glucose tolerance test; Procedure: aerobic capacity (VO2 Max); Drug: testosterone; Procedure: MRI; Drug: goserelin acetate implant; Drug: anastrozole; Procedure: muscle biopsy; Procedure: measurement of resting metabolic rate (energy expenditure); Procedure: Dual energy x-ray absorptiometry; Procedure: Fasting oral glucose tolerance test

• Registration Number: NCT00433173
• Lead Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Brief Summary

The metabolic syndrome is a medical condition defined by high levels of cholesterol in the blood, high blood pressure, central obesity (gain in fat around the region of the stomach), and insulin resistance (body responds less well to insulin). This state of impaired insulin resistance can lead to type 2 diabetes mellitus, which is one of the most common metabolic disorders in the U.S. Numerous studies have shown an inverse relationship between insulin resistance and testosterone levels in men, however, causality has not been established. This protocol investigates the role of testosterone in modulating insulin sensitivity in insulin resistant states such as the metabolic syndrome. The hypothesis is that testosterone administration will improve insulin sensitivity.

Detailed Description

This protocol will address the impact of three months of testosterone (T) therapy on all components of the metabolic syndrome and the mechanism underlying changes in insulin sensitivity by analyzing changes in body composition, and detailed studies of fat metabolism and skeletal muscle. In addition, this protocol will address the role of estradiol (E2) in mediating the effect of testosterone on insulin sensitivity.

Seventy-two subjects will be enrolled. Study subjects will undergo a screening visit to assess eligibility after which a baseline metabolic assessment will be performed including a a fasting oral glucose tolerance test (OGTT) to measure normal glucose and insulin metabolism, an intravenous glucose tolerance test (IVGTT) to measure insulin sensitivity, MRI and DEXA scan to assess muscle and body fat distribution, VO2 max test and resting metabolic rate, and a muscle biopsy to look at how the muscle is affected by insulin and testosterone (T).

Subjects will then be randomized to one of three 12-week treatment arms, 1) Group 1 (Placebo); 2) Group 2 (Depot GnRH agonist (Zoladex) + Testosterone + placebo); or 3) Group 3 (Zoladex + Testosterone + aromatase inhibitor (anastrozole)). The rationale for this study design is as follows. Under normal physiological conditions, administration of T leads to a concomitant increase in estradiol (E2) levels due to endogenous conversion by the aromatase enzyme system. Therefore, in order to understand the relative roles of T and E2 on insulin sensitivity, one group of subjects will receive T in conjunction with the aromatase inhibitor, anastrozole.

At 13 weeks, the entire baseline evaluation including OGTT, IVGTT, resting metabolic rate and VO2 max, body composition assessment by DEXA and MRI, and muscle biopsy will be repeated. Subjects will return for a follow up visit four weeks later to measure CBC, T and PSA levels, to ensure levels are within the normal range.

Study Timeline

• Study Start: 2006-05
• Study First Submitted: 2007-02-08
• Study First Submitted QC: 2007-02-08
• Study First Posted: 2007-02-09
• Status Verified: 2010-03
• Last Update Submitted: 2010-03-01
• Last Update Posted: 2010-03-02
• Primary Completion: 2011-02
• Study Completion: 2011-03

Recruitment & Eligibility

• Status: SUSPENDED
• Sex: Male
• Target Recruitment: 72

Inclusion Criteria

• Age 50-75 yr

• Diagnosis of the metabolic syndrome defined by the American Heart Association/National Heart, Lung, and Blood Institute guidelines as the presence of three or more of the following:

  • Waist circumference > 102 cm
  • Serum triglycerides > 150 mg/dL
  • HDL cholesterol < 40 mg/dL
  • Blood pressure > 130 mm Hg systolic or 85 mm Hg diastolic, or treatment with anti-hypertensives
  • Fasting serum glucose > 100 mg/dL
  • Plasma total testosterone level less than 300 ng/dL (1 SD below the mean for young healthy men)
  • Stable weight for previous three months (no weight change greater than or equal to +/-10 lbs)
  • Normal TSH, prolactin and prostate specific antigen (PSA) levels (<2.5 ng/mL)

Exclusion Criteria

• New diagnosis of type 2 diabetes as defined by the ADA criteria: fasting glucose greater than 126 mg/dL or random blood glucose greater than 200 mg/dL on two occasions, or on oral hypoglycemic agents

• Contraindication to stress testing

• Contraindication to MRI scanning (Central nervous system aneurysm clips; Implanted neural stimulator; Implanted cardiac pacemaker or defibrillator; Cochlear implant; Ocular foreign body (e.g. metal shavings); Insulin pump; Metal shrapnel or bullet)

• History of testicular disorders (i.e. cryptorchidism)

• History of bleeding disorders (i.e. thrombocytopenia) or baseline hemoglobin levels less than 12g/dL

• History of metabolic bone disease (osteoporosis, osteomalacia)

• History of prostate cancer

• History of sleep apnea (subjects will also be excluded if at their baseline assessment they admit to heavy snoring, restless sleep, and/or excessive daytime somnolence)

• Symptoms of urinary outflow obstruction (i.e. benign prostatic hypertrophy)

• Illicit drug use or heavy alcohol use (>4 drinks/day)

• Allergic disorders

• Current medications (must exclude individuals taking the following medications):

  • Testosterone,
  • Cimetidine,
  • Spironolactone,
  • Ketoconazole,
  • Finasteride,
  • DHEA,
  • Androstenedione,
  • Oral steroids,
  • GnRH analogs

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
1	intravenous glucose tolerance test	1) Group 1: Placebo
1	aerobic capacity (VO2 Max)	1) Group 1: Placebo
1	MRI	1) Group 1: Placebo
1	muscle biopsy	1) Group 1: Placebo
1	measurement of resting metabolic rate (energy expenditure)	1) Group 1: Placebo
1	Dual energy x-ray absorptiometry	1) Group 1: Placebo
1	Fasting oral glucose tolerance test	1) Group 1: Placebo
2	intravenous glucose tolerance test	2) Group 2: Depot GnRH agonist (Zoladex) + Testosterone + placebo
2	goserelin acetate implant	2) Group 2: Depot GnRH agonist (Zoladex) + Testosterone + placebo
2	aerobic capacity (VO2 Max)	2) Group 2: Depot GnRH agonist (Zoladex) + Testosterone + placebo
2	MRI	2) Group 2: Depot GnRH agonist (Zoladex) + Testosterone + placebo
2	muscle biopsy	2) Group 2: Depot GnRH agonist (Zoladex) + Testosterone + placebo
2	measurement of resting metabolic rate (energy expenditure)	2) Group 2: Depot GnRH agonist (Zoladex) + Testosterone + placebo
2	Dual energy x-ray absorptiometry	2) Group 2: Depot GnRH agonist (Zoladex) + Testosterone + placebo
2	Fasting oral glucose tolerance test	2) Group 2: Depot GnRH agonist (Zoladex) + Testosterone + placebo
3	intravenous glucose tolerance test	3) Group 3: (Zoladex + Testosterone + aromatase inhibitor (anastrozole)
3	goserelin acetate implant	3) Group 3: (Zoladex + Testosterone + aromatase inhibitor (anastrozole)
3	aerobic capacity (VO2 Max)	3) Group 3: (Zoladex + Testosterone + aromatase inhibitor (anastrozole)
3	MRI	3) Group 3: (Zoladex + Testosterone + aromatase inhibitor (anastrozole)
3	muscle biopsy	3) Group 3: (Zoladex + Testosterone + aromatase inhibitor (anastrozole)
3	measurement of resting metabolic rate (energy expenditure)	3) Group 3: (Zoladex + Testosterone + aromatase inhibitor (anastrozole)
3	Dual energy x-ray absorptiometry	3) Group 3: (Zoladex + Testosterone + aromatase inhibitor (anastrozole)
3	Fasting oral glucose tolerance test	3) Group 3: (Zoladex + Testosterone + aromatase inhibitor (anastrozole)
2	testosterone	2) Group 2: Depot GnRH agonist (Zoladex) + Testosterone + placebo
3	testosterone	3) Group 3: (Zoladex + Testosterone + aromatase inhibitor (anastrozole)
3	anastrozole	3) Group 3: (Zoladex + Testosterone + aromatase inhibitor (anastrozole)

Primary Outcome Measures

Name	Time	Method
insulin sensitivity	at baseline and after 3 months

Secondary Outcome Measures

Name	Time	Method
glucose metabolism	at baseline and after 3 months
body composition VO2 max; resting metabolic rate; muscle biopsy analysis	at baseline and after 3 months
VO2 max	at baseline and after 3 months
resting metabolic rate	at baseline and after 3 months
muscle biopsy analysis	at baseline and after 3 months

Trial Locations

Locations (2)

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Johns Hopkins Bayview Medical Center; 🇺🇸 Baltimore, Maryland, United States